Oxazaborolidinone-promoted vinylogous mukaiyama aldol reactions

Article abstract of DOI:10.1021/ol702640w

δ-Hydroxy-α,β-unsaturated carbonyl compounds were prepared in one step via the vinylogous Mukaiyama aldol reactions with O,O-silyl ketene acetals. Isopropyl alcohol as additive and tryptophane-based B-phenyloxazaborolidinone were required for obtaining th

Full text of DOI:10.1021/ol702640w

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5637-5639
Oxazaborolidinone-Promoted Vinylogous
Mukaiyama Aldol Reactions
Serkan Simsek, Melanie Horzella, and Markus Kalesse*
Institut fu¨r Organische Chemie, Leibniz UniVersita¨t HannoVer, Schneiderberg 1B,
30167 HannoVer, Germany
markus.kalesse@oci.uni-hannoVer.de
Received November 1, 2007
ABSTRACT
δ-Hydroxy-r,â-unsaturated carbonyl compounds were prepared in one step via the vinylogous Mukaiyama aldol reactions with O,O-silyl ketene
acetals. Isopropyl alcohol as additive and tryptophane-based B-phenyloxazaborolidinone were required for obtaining the
γ-alkylated product
in high enantioselectivities.
The increasing demand for new antibiotics and antitumor
compounds led to a growing interest in biologically active
Scheme 1. Regioselectivity in the VMAR
compounds. In particular, polyketides proved to be attractive
targets for biology-driven research. In this context, the rapid
and efficient total synthesis of these natural products becomes
increasingly important. Standard strategies for the construc-
tion of the polyketide framework parallel the biosynthesis
of these compounds where acetate or propionate unites are
joined.1 Despite the reliable predictability and broad ap-
plicability of aldol or aldol-like reactions, new methods for
the rapid access of larger polyketide frameworks could speed
up the synthesis of new compounds.
With this background, different approaches to install
stereoselective variations of the vinylogous Mukaiyama aldol
reaction (VMAR) or vinylogous aldol reactions in general
have been put forward, providing access to δ-hydroxy-R,â-
unsaturated esters or lactones.2-4 The vinylogous extension
of the aldol reactions is associated with regioselectivity issues
since addition to the ketene acetal can proceed in the R- or
γ-position (Scheme 1).5 We previously reported the tri-
arylborane-catalyzed VMAR with unsubstituted silyl ketene
acetals in high regio- and Felkin selectivities.6
Based on the wide range of applications for the vinylogous
Mukaiyama aldol reaction, enantioselective variations be-
came increasingly important, and we envisioned that amino
(3) (a) Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Chem. Pharm. Bull.
1994, 42, 839. (b) Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Heterocycles
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S. E.; Heemstra, J. R., Jr. J. Org. Chem. 2007, 72, 5668. (n) Heumann, L.
V.; Keck, G. E. Org. Lett. 2007, 9, 4275.
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(b) Staunton, J.; Weissman, K. J. Nat. Prod. Rep. 2001, 18, 380.
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G.; Rassu, G. Chem. ReV. 2000, 100, 1929.
10.1021/ol702640w CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/04/2007

isobutyraldehyde and ketene acetal 19 (Table 1). For the
construction of the OXB catalysts, the amino acids valine,
phenylalanine, and tryptophane were used. In initial experi-
ments, only the γ-addition products were isolated in 32-
44% yield (entries 1-3). While the use of OXB 3 only
generated racemic mixtures of 2, the OXBs 4 and 5 gave
enantioselectivities between 72 and 74%, independent of the
catalyst concentration.
Table 1. Enantioselective VMAR with Isobutyraldehyde and
Ketene Acetal 1 Catalyzed by OXBa
In order to suppress the competing pathway of carbonyl
activation through cationic silicon species,10 which would
result in racemic products (Scheme 2), isopropyl alcohol was
γ-product 2
Scheme 2. OXB-Activated Aldehyde vs Si+-Activated
entrya OXB (mol %) additive
γ/R
yieldc,d (%) eee (%)
Aldehyde
1
2
3
4b
5b
6b
7b,f
8b,f
9b,f
3 (20/100)
4 (20/100)
5 (20/100)
3 (20)
4 (20)
5 (20)
5 (20)
5 (50)
5 (100)
99:<1
99:<1
99:<1
99:<1
99:<1
99:<1
99:<1
99:<1
99:<1
38
44
32
31
46
32
44
63
75
0
72
74
0
83
96
96
97
98e,g
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
a 1.0 equiv of aldehyde and 1.2 equiv of ketene acetal 1. b 1.2 equiv of
additive. c Isolated yield after chromatography. d Additionally 3% racemic
TBS-protected γ-product. e Determined by (+)-Eu(hfc)3.11 f By simulta-
neous addition of the starting materials and the additive via syringe pump.
g Determined by chiral GC on TBS-protected compound.
used as a nucleophile. When the reaction was carried out
with isopropyl alcohol and 20 mol % of 5 (entries 5 and 6,
Table 1) an increase in enantioselectivity up to 96% was
observed, albeit in moderate chemical yields.
To improve the unexpected low yields, careful optimiza-
tion of the reaction conditions was required. Higher yields
were observed by simultaneous addition of the starting
materials and the additive via syringe pump. The use of
stoichiometric amounts of OXB 5 further improved the yield
up to 75% with concomitant increase of the enantioselectivity
to 98% ee (entry 9). On the other hand, changing the solvent
to EtCN or CH2Cl2 did not improve the yields.
The resulting configuration is consistent with the proposed
transition state for OXB-catalyzed aldol-type reactions
(Figure 1),8a,12 for which the observed configuration is based
on shielding of the aldehyde’s si-face through the indole
moiety. In our case, the initial theory based configurational
assignment was independently confirmed by the Mosher
method.13
acid based oxazaborolidinones7 should promote the VMAR
of ester-derived ketene acetals with high enantioselectivities.
One of the major advantages of oxazaborolidinones com-
pared to other chiral Lewis acids is their readily available
access from sulfonamides of R-amino acids and boranes.
Their valuable contribution to asymmetric synthesis was
demonstrated by applications of the Yamamoto8a and
Kiyooka8b protocol in Lewis acid catalyzed Mukaiyama aldol
reactions. In particular, applications with B-phenyloxazaboro-
lidinones were very effective in obtaining high yields and
selectivities.
Herein, we report the enantioselective vinylogous Mu-
kaiyama aldol reaction of O,O-silyl ketene acetals promoted
by B-phenyloxazaborolidinones (OXB). Our initial studies
to optimize the reaction conditions were performed using
(4) For applications of the vinylogous aldol reaction in the syntheses of
natural products, see: (a) Kru¨ger, J.; Carreira, E. M. Tetrahedron Lett. 1998,
39, 7013. (b) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J. A.;
Charette, A. B.; Lautens, M. J. Angew. Chem., Int. Ed. 1998, 37, 2354. (c)
Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.; Prunet, J. A.;
Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540. (d) Brennan, C. J.;
Campagne, J. M. Tetrahedron Lett. 2001, 42, 5195. (e) Bluet, G.; Campagne,
J. M. Synlett 2000, 221. (f) Snider, B. B.; Song, F. B. Org. Lett. 2001, 3,
1817. (g) Paterson, I.; Davies, R. D. M.; Heimann, A. C.; Marquez, R.;
Meyer, A. Org. Lett. 2003, 5, 4477. (h) Paterson, I.; Florence, G. J.;
Heimann, A. C.; Mackay, A. C. Angew. Chem., Int. Ed. 2005, 44, 1130.
(5) Shirokawa, S.-i.; Kamiyama, M.; Nakamura, T.; Okada, M.; Nakazaki,
A.; Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 13604.
(6) Christmann, M.; Kalesse, M. Tetrahedron Lett. 2001, 42, 1269.
(7) (a) Takasu, M.; Yamamoto, H. Synlett 1990, 194. (b) Sartor, D.;
Saffrich, J.; Helmchen, G. Synlett 1990, 197.
Next, we investigated the scope and limitations using
different aldehydes (Table 2). At this point, it should be
(9) Hoffman, R. V.; Kim, H. O. J. Org. Chem. 1991, 56, 1014.
(10) (a) Wang, X.; Adachi, S.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo,
M.; Oku, A.; Harada, T. J. Org. Chem. 2003, 68, 10046. (b) Carreira, E.
M.; Roberti, A. S. Tetrahedron Lett. 1994, 35, 4323. (c) Hassfeld, J.;
Christmann, M.; Kalesse, M. Org. Lett. 2001, 3, 3561.
(11) (a) Yeh, H. J. C.; Balani, S. K.; Yagi. H.; Greene, R. M. E.; Sharma,
N. D.; Boyd, D. R.; Jerina, D. M. J. Org. Chem. 1986, 51, 5439. (b)
Sweeting, L. M.; Crans, D. C.; Whitesides, G. M. J. Org. Chem. 1987, 52,
2273.
(12) (a) Corey, E. J.; Loh, T.-P. J. Am. Chem. Soc. 1991, 113, 8966. (b)
Corey, E. J.; Loh, T.-P. Tetrahedron Lett. 1993, 34, 3979. (c) Corey, E. J.;
Guzman-Perez, A.; Loh, T.-P. J. Am. Chem. Soc. 1994, 116, 3611.
(13) (a) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092.
(8) (a) Ishihara, K.; Kondo, S.; Yamamoto, H. J. Org. Chem. 2000, 65,
9125. (b) Kiyooka, S.-I.; Hena, M. A.; Yabukami, T.; Murai, K.; Goto, F.
Tetrahedron Lett. 2000, 41, 7511.
5638
Org. Lett., Vol. 9, No. 26, 2007

Scheme 3. Vinylogous Mukaiyama Aldol Reaction with
R-Chiral Aldehydes
Figure 1. Proposed transition state for the VMAR using N-Ts-L-
tryptophane.
pointed out that for many transformations aliphatics are the
more challenging substrates.
Here, very good yields and selectivities were observed for
aliphatic as well as for aromatic or unsaturated aldehydes.
As observed previously, the γ-product was again obtained
in high enantiomeric excess with only a small amount of
the R-product observed for unsaturated aldehydes.
In order to evaluate the practicability of the vinylogous
Mukaiyama aldol reaction in total syntheses, R-chiral alde-
hydes were additionally used as substrates. We observed that
the appropriate choice of protecting groups for high selectivi-
ties (Scheme 3). Here, the TBS ethers provided useful
selectivities in contrast to PMB-protected substrates. For
aldehydes obtained from the Roche ester, the matched and
mismatched case gave similar selectivities and yields,
indicating that the chiral Lewis acid overrides the inherent
Felkin selectivity. Aldehydes obtained from lactic acid on
the other hand did show a distinct different selectivity for
the matched and mismatched case. Here only on the matched
case provided useful results.
In summary, the use of tryptophane-derived B-phenyl-
oxazaborolidinone for the enantioselective vinylogous Mu-
kaiyama aldol reaction of O,O-silyl ketene acetal 1 provided
an efficient access to chiral building blocks for polyketide
synthesis. These studies additionally add to the general
picture that isopropyl alcohol is required as an additive for
suppressing the racemic TBS-catalyzed pathway and en-
hances the enantioselectivity. In cases of R-chiral aldehydes
it could be shown that the appropriate choice of protecting
groups is essential for high selectivities.
Table 2. VMAR on Different Aldehydes
R-product
γ-product
entry
aldehyde
yielda,b (%) yielda,b (%) ee (%)
Acknowledgment. We gratefully acknowledge the
Deutsche Forschungsgemeinschaft for financial support
(Ka 913/10-1).
1
2
3
4
5
6
pivalaldehyde
valeraldehyde
cyclohexylaldehyde
2-furylaldehyde
benzaldehyde
<1
4
<1
9
11
13
6 (65)
7 (70)
8 (80)
9 (66)
10 (60)
11 (63)
99c,d
94c,e
96c,e
83e
80c,e
76c,e
Supporting Information Available: Spectroscopic data
and experimental procedures for compounds 1, 2, 5-12, 14,
and 16. This material is available free of charge via the
Internet at http://pubs.acs.org.
E-cinnamaldehyde
a Isolated yield after chromatography. b Additional 4% of racemic TBS-
protected product. c Determined by (+)-Eu(hfc)3.11 d Determined by chiral
GC on the TBS-protected compound. e Determined by the Mosher method.
OL702640W
Org. Lett., Vol. 9, No. 26, 2007
5639